Process for the production of 2-(substituted benzoyl)-1,3 cyclohexanediones

ABSTRACT

A process for preparing a compound of formula (I), where R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are independently hydrogen or C 1-6  alkyl; R 7  is halogen, cyano, NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy or RaS in which Ra is C 1-4  alkyl; R 8 , R 9  and R 10  independently are hydrogen, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, CN, NO 2 , phenoxy or substituted phenoxy; R b  S(O)n Om in which m is 0 or 1, n is 0, 1 or 2 and Rb is C 1-4  alkyl, C 1-4  haloalkyl, phenyl or benzyl, NHCOR c  in which c is C 1-4  alkyl, NRdRe in which Rd and Re independently are hydrogen or C 1-4  alkyl; RfC(O)-- in which Rf is hydrogen, C 1-4  alkyl, C 1-4  haloalkyl or C 1-4  alkoxy; SO 2  NRgRh in which Rg and Rh independently are hydrogen or C 1-4  alkyl; or any two of R 8 , R 9  and R 10  together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic ring containing up to three heteroatoms selected from 0, N or S and which may be optionally substituted by C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, ═NOC 1-4  alkyl, or halogen; which process comprises the rearrangement of a compound of formula (II), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9  and R 10  are as defined in relation to formula (I), in the presence of a base and a polar aprotic solvent characterized in that the process is carried out in a reaction medium substantially free of hydrogen cyanide or cyanide anion. ##STR1##

The present invention relates to the production of 2-(substituted benzoyl)-1,3-cyclohexanedione compounds.

2-(substituted benzoyl)-1,3-cyclohexanediones are known as herbicides from for example U.S. Pat. No. 4,780,127, U.S. Pat. No. 4,806,146, U.S. Pat. No. 4,946,981, U.S. Pat. No. 5,006,158, WO 9408988 and WO 9404524. One method of producing these compounds is by re-arrangement of an enol ester. This method is described in U.S. Pat No. 4,780,127 and U.S. Pat. No. 4,695,673. In these rearrangement reactions the presence of hydrogen cyanide or cyanide anion is described as essential (generally in an amount of 1-10 mol percent with respect to the enol ester). In an industrial scale process it is desirable to avoid the use of such materials. Surprisingly it has now been found that in certain solvents it is possible to perform the rearrangement in the absence of hydrogen cyanide or cyanide anion.

According to the present invention there is provided a process for preparing a compound of formula (I) where R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen or C₁₋₆ alkyl; R⁷ is halogen, cyano, NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy or RaS in which Ra is C₁₋₄ alkyl; R⁸, R⁹ and R¹⁰ independently are hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl, CN, NO₂, phenoxy or substituted phenoxy; R_(b) S(O)nOm in which m is 0 or 1, n is 0, 1 or 2 and Rb is C₁₋₄ alkyl, C₁₋₄ haloalkyl, phenyl or benzyl, NHCOR_(c) in which Rc is C₁₋₄ alkyl, NRdRe in which Rd and Re independently are hydrogen or C₁₋₄ alkyl; RfC(O)-- in which Rf is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₁₋₄ alkoxy; SO₂ NRgRh in which Rg and Rh independently are hydrogen or C₁₋₄ alkyl; or any two of R⁸, R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic ring containing up to three heteroatoms selected from O, N or S and which may be optionally substituted by C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, ═NOC₁₋₄ alkyl or halogen; which process comprises the rearrangement of a compound of formula (II) where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as defined in relation to formula (I), in the presence of a base and a polar aprotic solvent characterised in that the process is carried out in a reaction medium substantially free of hydrogen cyanide or cyanide anion.

As used herein the term "alkyl", refers to straight or branched chains. The term "haloalkyl" refers to an alkyl group substituted by at least one halogen. Similarly the term "haloalkoxy" refers to an alkoxy group substituted by at least one halogen. As used herein the term "halogen" refers to fluorine, chlorine, bromine and iodine.

Suitable optional substituents for phenoxy groups R⁸, R⁹ and R¹⁰ include halogen such as fluorine and chlorine and C₁₋₄ haloalkyl.

A preferred group of compounds of formula (I) are those where R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen or C₁₋₆ alkyl; R⁷ is halogen, cyano, NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy or RaS in which Ra is C₁₋₄ alkyl; R⁸, R⁹ and R¹⁰ independently are hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, NO₂, phenoxy or substituted phenoxy; R_(b) S(O)nOm in which m is 0 or 1, n is 0, 1 or 2 and Rb is C₁₋₄ alkyl, C₁₋₄ haloalkyl, phenyl or benzyl, NHCOR_(c) in which Rc is C₁₋₄ alkyl, NRdRe in which Rd and Re independently are hydrogen or C₁₋₄ alkyl; RfC(O)-- in which Rf is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₁₋₄ alkoxy; or SO₂ NRgRh in which Rg and Rh independently are hydrogen or C₁₋₄ alkyl.

Preferably R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen or C₁₋₄ alkyl. More preferably R¹, R², R⁵ and R⁶ are hydrogen and R³ and R⁴ are independently hydrogen or methyl.

R⁷ is preferably halogen or NO₂. A preferred value for R⁸ is hydrogen.

R⁹ is preferably hydrogen or C₁₋₄ alkoxy, especially ethoxy. Most preferably R⁹ is hydrogen.

Preferably R¹⁰ is a group RbS(O)_(n) Om where Rb, n and m are as defined above. More preferably m is zero, n is 2 and Rb is CH₃ or C₂ H₅. Most preferably R¹⁰ is a group CH₃ SO₂ attached to the benzoyl group at the 4-position.

Suitable bases include both organic bases such as trialkylamines and inorganic bases such as alkali metal carbonates and phosphates. The trialkylamines are preferably tri(lower alkyl)amines having from 1 to 6, preferably 1 to 4 carbon atoms per alkyl group. A particularly preferable amine is triethylamine. Suitable inorganic bases include sodium carbonate, potassium carbonate and trisodium phosphate. Even a bicarbonate such as potassium bicarbonate will function effectively in this reaction when used in combination with a dipolar aprotic solvent such as dimethylformamide. Preferred bases are sodium carbonate and potassium carbonate.

The base is used in an amount of from about 1 to about 4 moles per mole of enol ester, preferably about 2 moles per mole.

As used herein the expressions "substantially free of hydrogen cyanide or cyanide anion" means that neither of these moieties is deliberately added to the reaction medium.

Preferred solvents for the process are acetonitrile, dimethylformamide, tetrahydrofuran and mixtures of these solvents with non-polar solvents such as toluene and xylene.

In general, depending on the nature of the reactants, the base and the solvent the rearrangements may be conducted at temperatures from 0° C., up to about 100° C. Preferably the temperature is at a maximum of about 80° C. Most preferably the temperature is from about 20° C., to about 70° C. In some cases, for instance when there is a possible problem of excessive by-product formation (for instance, when using an orthonitro benzoyl halide) the temperature should be kept at about 40° C. maximum.

The process may be carried out using the enol ester as the starting material, or with generation of the enol ester in situ, for instance by reaction of a compound of formula (III) where R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in relation to formula (I) with a compound of formula (IV) where R⁷, R⁸, R⁹ and R¹⁰ are as defined in relation to formula (I) and Z is a halo, preferably chloro.

When the enol ester is utilised as a starting material it may be prepared by any of a number of known means, including acylation of a compound of formula (III) with, a compound of formula (IV).

The production of compounds of formula (I) according to this invention, may be advantageously carried out starting with compounds of formula (III) and formula (IV) may be carried out with or without isolation of the intermediate enol ester. When carried out in two steps, the compound of formula (III) and the compound of formula (IV) are reacted in the presence of a moderate base such as sodium carbonate or triethylamine. The enol ester isolated from the resulting product mix by known techniques, for instance washing the resultant solution with acid and base, and with saturated sodium chloride solution, and drying. Such a technique is advantageous when a different solvent is preferred for the second step--the rearrangement of the enol ester to the compound of formula (I). The dried enol ester may be mixed with an appropriate solvent such as acetonitrile, or tetrahydrofuran and contacted with the appropriate amounts of moderate base and heated to an temperature, to produce the final product.

Alternatively, the enol ester may be retained in the reaction product and the second stage may be carried out (using the same solvent) by adding additional base if necessary to produce the compound of formula (I).

Comparable yields can be obtained either with or without isolation of the enol ester.

The compound of formula (I) is obtained from this reaction in the form of its salt. The desired acylated compound of formula (I) may be obtained with acidification and extraction with an appropriate solvent.

The process of the invention is illustrated by the following example.

EXAMPLE 1

Acetonitrile (25 g) was charged to a 4 necked 250 ml flamed dried round bottom flask previously purged with N₂ and sealed to a Drierite guard tube and oil bubbler. 1,3 cyclohexanedione (5.0 g) and sodium carbonate powder (12.0 g) were charged to give a red slurry. This mass was heated to 55°-57° C. and held for 20 minutes. 2-chloro-4-(methylsulphonyl)benzoyl chloride (11.0 g) was added to acetonitrile (25 g) and warmed gently to obtain a complete solution. This solution was added to the mass dropwise over 20 minutes at 55°-57° C. to give a pale yellow slurry. The mass was held at 55°-57° C. for 17 hours. The required compound of formula (I) as the sodium salt was produced in 82% yield.

EXAMPLE 2

In a second example the acetronitrile in Example 1 was replaced by dimethylformamide and the sodium carbonate was replaced with an equimolar amount of potassium carbonate. Following the same procedures, the reaction was complete 20 minutes after the acid chloride additions was ended and the yield of the required compound of formula (I) as the potassium salt was 54%.

EXAMPLE 3

The procedure of Example 1 was repeated using triethylamine in place of sodium carbonate and DMF in place of acetonitrile. The reaction was complete after 4 hours with a yield of 45%.

CHEMICAL FORMULAE (In Description) ##STR2## 

We claim:
 1. A process for preparing a compound of formula (I):where R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen or C₁₋₆ alkyl; R⁷ is halogen, cyano, NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy or R_(a) S in which R_(a) is C₁₋₄ alkyl; R⁸, R⁹ and R¹⁰ independently are hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, NO₂, phenoxy or substituted phenoxy; R_(b) S(O)n Om in which m is 0 or 1, n is 0, 1 or 2 and R_(b) is C₁₋₄ alkyl, C₁₋₄ haloalkyl, phenyl or benzyl, NHCOR_(c) in which R_(c) is C₁₋₄ alkyl, NRdRe in which R_(d) and R_(e) independently are hydrogen or C₁₋₄ alkyl; R_(f) C(O)-- in which R_(f) is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₁₋₄ alkoxy; SO₂ NR_(g) R_(h) in which R_(g) and R_(h) independently are hydrogen or C₁₋₄ alkyl; or any two of R⁸, R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 5 or 6 membered heterocyclic ring containing up to three heteroatoms selected from O, N or S and which may be optionally substituted by C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, ═NOC₁₋₄ alkyl, or halogen; which process comprises the rearrangement of a compound of formula (II): ##STR3## where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as defined in relation to formula (I), in the presence of a base and a polar aprotic solvent characterised in that the process is carried out in a reaction medium substantially free of hydrogen cyanide or cyanide anion.
 2. A process according to claim 1 where R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen or C₁₋₆ alkyl; R⁷ is halogen, cyano, NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy or R_(a) S in which R_(a) is C₁₋₄ alkyl; R⁸, R⁹ and R¹⁰ independently are hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, NO₂, phenoxy or substituted phenoxy; R_(b) S(O)n Om in which m is 0 or 1, n is 0, 1 or 2 and R_(b) is C₁₋₄ alkyl, C₁₋₄ haloalkyl, phenyl or benzyl, NHCOR_(c) in which R_(c) is C₁₋₄ alkyl, NR_(d) R_(e) in which R_(d) and R_(e) independently are hydrogen or C₁₋₄ alkyl; R_(f) C(O)-- in which R_(f) is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₁₋₄ alkoxy; or S₂ NR_(g) R_(h) in which R_(g) and R_(h) independently are hydrogen or C₁₋₄ alkyl.
 3. A process according to claim 1 where R¹, R², R⁵ and R⁶ are hydrogen and R³ and R⁴ are independently hydrogen or methyl.
 4. A process according to claim 1 where R⁷ is halogen or NO₂.
 5. A process according to claim 1 where R⁸ is hydrogen.
 6. A process according to claim 1 where hydrogen or C₁₋₄ alkoxy.
 7. A process according to claim 1 where R¹⁰ is a group CH₃ SO₂ attached to the benzoyl group at the 4-position.
 8. A process according to claim 1 where the solvent is acetonitrile, dimethylformamide, tetrahydrofuran or mixtures of these solvents with toluene or xylene.
 9. A process according to claim 1 where the base is triethylamine, sodium carbonate or potassium carbonate. 